Waldmann co-discovered the cytokine IL-15 and elucidated its role in the development of NK cells and CD8 memory phenotype T-cells. He demonstrated that IL-15 acts as a cell-membrane associated molecule, that IL-15R alpha on antigen-presenting cells (APCs) presents IL-15 in trans to NK and CD8 T-cells. Waldmann demonstrated IL-15 to be of value in 4 murine models of neoplasia. IL-15 administered by continuous intravenous infusion (CIV) at 20 mcg/kg for 10 days to rhesus macaques was associated with an 80-100-fold increase in the number of circulating CD8 effector memory T-cells. Waldmann and Kevin Conlon, using IL-15 produced at the NCI, performed the first-in-human trial of rhIL-15. Five of 18 patients manifested a decrease in marker lesions, with 2 having clearing of lung lesions. A collaborative trial with the Cancer Immunotherapy Network (CITN) of subcutaneous Escherichia coli rhIL-15 has been completed where the MTD was 3 mcg/kg/day. In a trial performed by Waldmann and Conlon a dose escalation of IL-15 by CIV was completed in patients with metastatic malignancy with the MTD of 2 mcg/kg/day. In this trial there was initially an efflux of NK cells from the circulation followed on termination of the CIV administration by a 30-fold increase in the number of circulating NK cells and an over 200-fold increase in the number of CD56bright NK cells. A particular challenge with rhIL-15 is that there is a low-level expression of IL-15R alpha on antigen-presenting cells including DCs. IL-15 and IL-15R alpha are always produced and expressed together. To address this issue, the IL-15 and IL-15R alpha combination is being evaluated in a clinical trial. An additional major scientific effort with IL-15 involves the evaluation of combination therapy with IL-15 and other agents in preclinical models and in clinical trials. Normally generation of antigen-specific CD8 T-cells utilizes an initial step involving antigen-bound CD4 cells with APCs, followed by interaction of CD8 T-cells with these APCs. An agonistic anti-CD40 antibody can substitute for the initial interaction of APCs with CD4 T- cells. Waldmann demonstrated that the combination of IL-15 with an agonistic anti-CD40 antibody showed additivity/synergy in 2 murine tumor models. The combination circumvented the problem of helpless CD8 T-cells wherein the CD8 T-cells produced are not tumor-antigen specific. Administration of the combination of IL-15 plus the agonistic anti-CD40 antibody but not the individual agents was associated with a marked increase in TRAMP C2 tumor specific tetramer positive CD8 T-cells. Ravetch and Waldmann are translating this observation into a clinical trial involving an optimized agonistic anti-CD40 antibody used in combination with rhIL-15 for patients with metastatic malignancy. Waldmann, Conlon and Alice Chan are initiating a trial translating preclinical studies of the Waldmann Laboratory that use IL-15 in combination with anti-CTLA-4, lymphocyte antigen-4 (CTLA-4) and anti-program death-1 (PD-L1). An additional group of studies involves combination therapy with IL-15 in association with anticancer monoclonal antibodies to augment antibody-dependent cell mediated cytotoxicity (ADCC). The predominant approach involving IL-15 is based on the hypothesis that the host is making an immune response albeit inadequate to tumor, and that this can be augmented by administration of IL-15. Given the capacity to increase the number of activated NK cells, a strategy is being evaluated wherein IL-15 is used in combination with antitumor monoclonal antibodies to augment their ADCC. In preclinical studies the Waldmann Group demonstrated markedly augmented ADCC and antitumor efficacy when IL-15 was added to antitumor monoclonal antibodies. A clinical trial has been initiated involving IL-15 with alemtuzumab in the treatment of patients with acute adult T-cell leukemia (ATL). Identify disorders of IL-15 in disease, and evaluate treatments using novel agents targeting the IL-15 receptor binding or IL-15 signaling. The studies we have just discussed focus on augmenting IL-15 action to increase patient immune responses to their tumor. The Waldmann Laboratory has also initiated a major program with the opposite goal of diminishing the action of IL-15 in situations where disorders of IL-15 play a role. Abnormalities of IL-15 expression have been described in refractory celiac disease, type 1 diabetes, cutaneous T-cell lymphoma, and in diseases associated with HTLV-1. The Waldmann Group has initiated collaborations to explore Mik-Beta-1, anti-IL-2/IL-15 directed monoclonal antibody produced at the NIH to block IL-15 binding in patients with refractory celiac disease and associated CD8 T-cell lymphoma (EATL). In addition, Waldmann has entered into collaborations evaluating AZ3, a pure JAK1 inhibitor, JAK3i, a pure JAK3 inhibitor, and H2-RETR and BMZ-1 small-molecule agents that bind respectively either to IL-2/IL-15R beta alone or yc alone to block both IL-15 and IL-2 actions. In summary, the Waldmann Laboratory has made major contributions to the evaluation of IL-15 in the treatment of patients with metastatic malignancy and into therapy-directed disorders of IL-15.